Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase Journal Article

   

Authors:	Kelly, M. P.; Jungbluth, A. A.; Wu, B. W.; Bomalaski, J.; Old, L. J.; Ritter, G.
Article Title:	Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase
Abstract:	Background: Some cancers have been shown to lack expression of argininosuccinate synthetase (ASS), an enzyme required for the synthesis of arginine and a possible biomarker of sensitivity to arginine deprivation. Arginine deiminase (ADI) is a microbial enzyme capable of efficiently depleting peripheral blood arginine. Methods: Argininosuccinate synthetase expression was assessed in human small cell lung cancer (SCLC) by immunohistochemistry (IHC), with expression also assessed in a panel of 10 human SCLC by qRT-PCR and western blot. Proliferation assays and analyses of apoptosis and autophagy assessed the effect of pegylated ADI (ADI-PEG20) in vitro. The in vivo efficacy of ADI-PEG20 was determined in mice bearing SCLC xenografts. Results: Approximately 45% of SCLC tumours and 50% of cell lines assessed were negative for ASS. Argininosuccinate synthetase-deficient SCLC cells demonstrated sensitivity to ADI-PEG20, which was associated with the induction of autophagy and caspase-independent cell death. Arginine deiminase-PEG20 treatment of ASS-negative SCLC xenografts caused significant, dose-dependent inhibition of tumour growth of both small and established tumours. Conclusion: These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this therapeutic approach in patients with ASS-negative SCLC by IHC has now been initiated. © 2012 Cancer Research UK All rights reserved.
Keywords:	immunohistochemistry; controlled study; protein expression; unclassified drug; human cell; drug activity; drug efficacy; nonhuman; sensitivity analysis; cell proliferation; mouse; animal tissue; cell death; reverse transcription polymerase chain reaction; apoptosis; lung neoplasms; animal experiment; animal model; rna, small interfering; tumor xenograft; caspase; cell line, tumor; cancer inhibition; lung small cell cancer; blotting, western; western blotting; base sequence; gene silencing; dna primers; autophagy; in vivo; small cell lung carcinoma; sclc; hydrolases; argininosuccinate synthase; real-time polymerase chain reaction; arginine deiminase; argininosuccinate synthetase; arginine deiminase peg20; auxotrophy
Journal Title:	British Journal of Cancer
Volume:	106
Issue:	2
ISSN:	0007-0920
Publisher:	Nature Publishing Group
Date Published:	2012-01-17
Start Page:	324
End Page:	332
Language:	English
DOI:	10.1038/bjc.2011.524
PROVIDER:	scopus
PMCID:	PMC3261683
PUBMED:	22134507
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84856458783&partnerID=40&md5=528f70c4ae731d7f5fa1175e70a3b31b
Notes:	--- - "Export Date: 1 March 2012" - "CODEN: BJCAA" - "Source: Scopus"

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